Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

TitleDevelopmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2013
AuthorsTanori, Mirella, Pasquali Emanuela, Leonardi Simona, Casciati Arianna, Giardullo Paola, De Stefano Ilaria, Mancuso Mariateresa, Saran Anna, and Pazzaglia Simonetta
JournalStem Cells
Keywordsanimal cell, animal experiment, animal model, animal tissue, Animals, Apoptosis, article, brain development, carcinogenesis, caspase 3, cell differentiation, cell migration, Cell Survival, cerebellum, controlled study, DNA damage, DNA repair, Embryo, embryonic stem cell, genotoxicity, granule cell, heterozygosity loss, immunohistochemistry, in vivo study, Inbred C57BL, Knockout, low energy radiation, medulloblastoma, Mice, mouse, nerve cell differentiation, nervous system development, neural stem cell, Neural stem cells, newborn, nonhuman, p21, Phenotype, Progenitor cells, progeny, protein bcl 2, protein expression, protein Patched 1, Ptc1+/- mice, radiation dose, Radiation exposure, radiation hazard, radiation injury, radiation response, radiosensitivity, Stem cells, X ray

Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1+/-) provide a powerful model of medulloblas-toma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1 +/- mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate-restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors. ©C AlphaMed Press.


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